Why we study inherited cancer risk

29Oct2017

Following their recent publication in Nature Reviews Cancer, the ICR’s Dr Amit Sud and Dr Ben Kinnersley explain why studying genetic susceptibility is a crucial aspect of cancer research, and how their work fits into our mission to defeat cancer.

Posted on 29 October, 2017by Dr Amit Sud and Dr Ben Kinnersley

Cancer touches the lives of almost everyone. But why do some get cancer and some don’t? How much of the ‘blame’ can be placed on lifestyle choices, and how much is it to do with the DNA we were born with?

The research of our group seeks to identify and characterise changes in what we call our ‘germline’ DNA – the DNA we inherit from our parents – to work out how these might increase a person’s cancer risk.

From studies over the last century it is clear that the majority of cancers have an inherited component. The link was first acknowledged in 1913 by a scientist called Aldred Scott Warthin, who described three families with many individuals affected with cancer, and found that the cases appeared to be inherited, relatives of cancer patients being at increased risk of getting cancer themselves.

Studies from the 1980s onwards have led to the identification of many what we call ‘high penetrance’ cancer susceptibility genes – genes that, if mutated, have a strong effect on a person’s risk of developing cancer, such as BRCA1/BRCA2 or p53.

Cancer is a very common disease but only a small number of people harbour this type of large-effect genetic mutation – less than 1% of the population.

So if at least part of the risk of developing cancer is related to our genes, there must be another explanation as to why relatives affected with cancer are at increased risk of developing cancer.

Our research

The majority of inherited cancer risk is thought to be explained by genetic variants that only have a small effect on our likelihood of developing cancer, but are much more common in the population – in upwards of 5% of people. If you have several variants, your risk of cancer increases.

These variants can be discovered through genome-wide association studies (GWAS), which is a focus of our group. GWAS analyses allow us to compare the frequency of millions of genetic variants, which occur in the human genome, between thousands of cancer cases and people without the disease.

Much of these common variants with small effects have been discovered over the past 10 years (and are still ongoing), with current estimates of at least 450 variants across more than 25 tumour types associated with cancer risk – including most common forms of cancer, including breast, bowel (colorectal), prostate and lung cancer as well as less common forms such as glioma, Hodgkin lymphoma and myeloma.

Why we do it

We study a multitude of cancers, several of which are tumour types of unmet need and for which current treatments are ineffective, limited and/or lacking. We believe studying genetic predisposition is a crucial aspect of cancer research for three main reasons:

1. Earlier diagnosis increases chance of survival

For certain common cancers, there is a rationale for using genetic data to help identify people at greater risk of cancer and therefore who would receive benefit from surveillance.

In isolation, common cancer risk mutations confer a small increase in cancer risk, but when acting in concert, the risk of cancer can be relatively substantial. This genetic information can be used in populations to inform screening programmes, with the aim of earlier detection of cancer in individuals that have an increased risk.

For example, colorectal cancers identified and treated at stage 1 have around 90 per cent survival after five years compared to 11% at stage 4. By monitoring people at high risk, it might be possible to catch it earlier.

2. Investigating associations helps us understand cancer biology

For all cancers there is a huge benefit in researching what changes these cancer risk variants cause inside cells. The majority of risk variants identified so far reside in regions of DNA that don’t contain genes.

Determining the likely cause is an ongoing challenge being tackled by many research groups, including ours. Our knowledge of how cells regulate gene activity through DNA folding and protein binding has provided insights into how common genetic variation increases cancer risk.

It is becoming increasingly clear that for many cancers, after one or several initial "driver" events, the patterns of mutations as tumours evolve becomes complex. This provides further rationale for studying cancer genetic susceptibility variants, which are presumed to exert their effects at the earliest stages of tumour development.

3. Informing discovery and development of new, innovative cancer therapies

We hope that study of cancer susceptibility will lead to discovery of molecular pathways that are recurrently altered in cancer cells and provide new opportunities for therapeutic intervention.

Drugs discovered based on supporting genetic evidence have been demonstrated to have greater success.

This is a topic we have begun to look into with Dr Bissan Al-Lazikani and her team at the ICR this year. Several cancer risk variants are found within areas of DNA containing genes known to be highly mutated in tumours, and which are already drug targets, for example a variant in the EGFR gene in glioma.

It is plausible that these DNA regions harbour equally important (but currently unappreciated) genes important in cancer, but need further research to work out their importance.

We can also use genetic data to help predict how people respond to treatment and what unwanted side-effects they may develop. This can help when deciding what treatment would give patients the maximum benefit.

We rely on the support of our donors to help fund training for the next generation of young scientists and clinicians who will go on to be leaders in cancer research.

But it’s not just about genetics…

Whilst our work is focused on genetic risk factors for cancer, the data we generate can also be used to study non-genetic risk factors for cancer, such as obesity. These studies can help in designing public health initiatives to help prevent cancer developing in some people.

Although great advances have been made in identifying genetic risk factors for cancer, progress needs to be made in understanding how these genes influence our risk.

There are still lots of gaps in our understanding of basic molecular biology which need to be addressed. Such work will require a ‘team science’ approach where scientists from different backgrounds such as chemistry and physics, use complementary skills and knowledge to work together to solve a problem.

We are extremely grateful to all the research charities who have funded us and the thousands of people who have provided us with samples, without whom our work would not be possible.

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